Differential efficacy of initial versus sequential combination of denosumab and teriparatide in osteoporosis at high fracture risk

For patients already on denosumab, adding teriparatide is a suboptimal last resort: it offers limited spinal benefit but carries a significant risk of hip bone loss, mandating a site-specific risk-benefit assessment.Background The management of patients with osteoporosis who exhibit a suboptimal response to denosumab remains clinically challenging. Adding teriparatide to established denosumab therapy is not well defined for high-risk patients in real-world settings.Objective This study aimed to directly compare the 12-month effects on bone mineral density (BMD) and bone turnover markers between an "initial combination" versus "sequential combination" (adding teriparatide to ongoing denosumab) in a cohort of postmenopausal women at high fracture risk.Methods In this 1-year retrospective cohort study, patients were assigned to one of two groups based on treatment history: the initial combination group (n = 54), in which teriparatide was initiated within 6 months of starting denosumab, and the sequential combination group (n = 25), in which teriparatide was added after more than 6 months of continuous denosumab monotherapy. The primary outcome was the percent change in lumbar spine (L1-L4) BMD.Results The mean increase in lumbar spine BMD was significantly greater in the initial combination group (+13.4%; 95% CI 9.9 to 22.5%) compared with the sequential combination group (+8.3%; 95% CI 1.9 to 9.2%; P = 0.030). A critical divergence was observed at the total hip. The initial combination group showed an increase in BMD (+6.0%; 95% CI -0.5 to 12.2%), whereas the sequential combination group experienced a significant decrease (-5.1%; 95% CI -7.1 to -3.9%; P = 0.009). Bone turnover markers (P1NP and CTX) were markedly elevated in the sequential combination group compared to the initial combination group (both P Conclusion Initial combination is optimal, while if sequential combination is necessary, it requires caution and may be more suitable for patients with predominant vertebral risk, mandating a site-specific benefit-risk assessment.